Effects of repeated exposure to MDMA on 5HT1a autoreceptor function: behavioral and neurochemical responses to 8-OHDPAT

Schenk, Susan; Abraham, Blaine; Aronsen, Dane; Colussi-Mas, Joyce; Do, Jennifer

doi:10.1007/s00213-013-2980-5

Cited by 8 publications

(8 citation statements)

References 42 publications

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“…We measured the accumulation of 5-HTP following decarboxylase inhibition and treatment with various doses of the 5HT 1a agonist, 8-OHDPAT. As expected, 5-HTP accumulation was dose-dependently decreased by 8-OHDPAT but this decrease was not modified by MDMA pretreatment, suggesting that 5HT 1a autoreceptors are not down-regulated by MDMA treatment (Schenk et al, 2013).…”

Section: Effec Ts Of Repe Ated Mdma On Neurotr Ans Miss Ionsupporting

confidence: 76%

“…Others found no reduction in 5HT syndrome following MDMA treatment (Granoff & Ashby, 2001). MDMA pretreatment also failed to alter 5-HT 1a -produced changes in lower lip retraction and hypolocomotion, two behaviors believed to reflect 5HT 1a autoreceptor activity (Schenk et al, 2013). The failure of MDMA treatment to impact 5HT 1a -mediated behaviours is consistent with the finding MDMA self-administration did not alter the dose-response curve for 5HT 1a agonist-produced locomotor activity .…”

Section: Effec Ts Of Repe Ated Mdma On Neurotr Ans Miss Ionsupporting

confidence: 65%

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Methylenedioxymethamphetamine (MDMA): Serotonergic and dopaminergic mechanisms related to its use and misuse

Schenk

Highgate

2021

Journal of Neurochemistry

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Methylenedioxymethamphetamine (MDMA) is an amphetamine analogue that preferentially stimulates the release of serotonin (5HT) and results in relatively small increases in synaptic dopamine (DA). The ratio of drug-stimulated increases in synaptic DA, relative to 5HT, predicts the abuse liability; drugs with higher DA:5HT ratios are more likely to be abused. Nonetheless, MDMA is a drug that is misused. Clinical and preclinical studies have suggested that repeated MDMA exposure produces neuroadaptive responses in both 5HT and DA neurotransmission that might explain the development and maintenance of MDMA self-administration in some laboratory animals and the development of a substance use disorder in some humans. In this paper, we describe the research that has demonstrated an inhibitory effect of 5HT on the acquisition of MDMA self-administration and the critical role of DA in the maintenance of MDMA self-administration in laboratory animals. We then describe the circuitry and 5HT receptors that are positioned to modulate DA activity and review the limited research on the effects of MDMA exposure on these receptor mechanisms.

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Section: Effec Ts Of Repe Ated Mdma On Neurotr Ans Miss Ionsupporting

confidence: 76%

Section: Effec Ts Of Repe Ated Mdma On Neurotr Ans Miss Ionsupporting

confidence: 65%

Methylenedioxymethamphetamine (MDMA): Serotonergic and dopaminergic mechanisms related to its use and misuse

Schenk

Highgate

2021

Journal of Neurochemistry

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“…It is still controversial which 5-HT 1A Rs namely pre- or postsynaptic are responsible for the induction of decrease in the body temperature in rats. Some data [23, 40, 41] suggest that postsynaptic rather than presynaptic 5-HT 1A R is implicated in this effect in rats. Despite that these data further suggest the agonist-like profile of Zn at 5-HT 1A R as in mice.…”

Section: Discussionmentioning

confidence: 99%

Concentration-Dependent Dual Mode of Zn Action at Serotonin 5-HT1A Receptors: In Vitro and In Vivo Studies

et al. 2015

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Recent data has indicated that Zn can modulate serotonergic function through the 5-HT1A receptor (5-HT1AR); however, the exact mechanisms are unknown. In the present studies, radioligand binding assays and behavioural approaches were used to characterize the pharmacological profile of Zn at 5-HT1ARs in more detail. The influence of Zn on agonist binding to 5-HT1ARs stably expressed in HEK293 cells was investigated by in vitro radioligand binding methods using the agonist [3H]-8-OH-DPAT. The in vivo effects of Zn were compared with those of 8-OH-DPAT in hypothermia, lower lip retraction (LLR), 5-HT behavioural syndrome and the forced swim (FST) tests. In the in vitro studies, biphasic effects, which involved allosteric potentiation of agonist binding at sub-micromolar Zn concentrations and inhibition at sub-millimolar Zn concentrations, were found. The in vivo studies showed that Zn did not induce LLR or elements of 5-HT behavioural syndrome but blocked such effects induced by 8-OH-DPAT. Zn decreased body temperature in rats and mice; however, Zn failed to induce hypothermia in the 5-HT1A autoreceptor knockout mice. In the FST, Zn potentiated the effect of 8-OH-DPAT. However, in the FST performed with the 5-HT1A autoreceptor knockout mice, the anti-immobility effect of Zn was partially blocked. Both the binding and behavioural studies suggest a concentration-dependent dual mechanism of Zn action at 5-HT1ARs, with potentiation at low dose and inhibition at high dose. Moreover, the in vivo studies indicate that Zn can modulate both presynaptic and postsynaptic 5-HT1ARs; however, Zn’s effects at presynaptic receptors seem to be more potent.

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“…Studies investigating CSF 5-HIAA concentrations in recreational users [Ricaurte et al 1990; McCann et al 1994] have consistently reported decreased levels of the metabolite, repeating animal literature, but these demonstrations come from polydrug users with unknown dosing. Tryptophan hydroxylase (Tph) activity also diminishes post-MDMA exposure [Bonkale and Austin, 2008, Schenk et al 2013], although these measurements have rarely exceeded 2 weeks in studies. Furthermore, a recent rodent study found that diminished Tph after MDMA administration is transient and can recover in all brain regions [Adori et al 2011].…”

Section: Mdma Pharmacologymentioning

confidence: 99%

MDMA for the treatment of mood disorder: all talk no substance?

Patel¹,

Titheradge²

2015

Therapeutic Advances in Psychopharmacology

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2007]. This postulate is based on the acute pharmacology of MDMA and is consistent with the hallmark theory of depression, the monoamine hypothesis [Krishnan and Nestler, 2008]. MDMA rapidly increases availability of extracellular 5-hydroxytryptamine (5-HT) at the synapse, mirroring the action of commonly prescribed antidepressants. However, current first-line treatments for depression, such as selective serotonin reuptake inhibitors (SSRIs), typically take about 6 weeks to produce optimum therapeutic change [Frazer and Benmansour, 2002]; MDMA could offer instantaneous relief. This rapid onset is an attractive prospect for treatment-resistant depression (TRD), where currently the only therapeutic option is electroconvulsive therapy (ECT). Although there is a theoretical basis, at present experimental evidence of antidepressant action of MDMA is low, with just one rodent [Majumder et al. 2011] and one volunteer study [Majumder et al. 2012] suggesting direct rapid-onset antidepressant action. MDMA is a controlled substance in most countries, typically in the most restrictive category (Class A in the UK). Despite this, MDMA is already in clinical trials for anxiety disorders such as post-traumatic stress disorder (PTSD), as an adjunct to psychotherapy where it is thought to assist therapy sessions by strengthening the

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Effects of repeated exposure to MDMA on 5HT1a autoreceptor function: behavioral and neurochemical responses to 8-OHDPAT

Cited by 8 publications

References 42 publications

Methylenedioxymethamphetamine (MDMA): Serotonergic and dopaminergic mechanisms related to its use and misuse

Methylenedioxymethamphetamine (MDMA): Serotonergic and dopaminergic mechanisms related to its use and misuse

Concentration-Dependent Dual Mode of Zn Action at Serotonin 5-HT1A Receptors: In Vitro and In Vivo Studies

MDMA for the treatment of mood disorder: all talk no substance?

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